Lack of CYP3A4 protein induction despite mRNA induction in primary hepatocytes exposed to rifabutin as a possible explanation for its low interaction risk in vivo
Rifampicin is a strong inducer of cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp/ABCB1), leading to profound drug-drug interactions. In contrast, the chemically related rifabutin does not show such pronounced induction properties in vivo. The aim of our study was to conduct a comprehensive analys...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
7 May 2024
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| In: |
Archives of toxicology
Year: 2024, Jahrgang: 98, Heft: 8, Pages: 2541-2556 |
| ISSN: | 1432-0738 |
| DOI: | 10.1007/s00204-024-03763-w |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00204-024-03763-w
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| Verfasserangaben: | Julie Nilles, Dirk Theile, Johanna Weiss, Walter E. Haefeli, Stephanie Ruez |
MARC
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| 245 | 1 | 0 | |a Lack of CYP3A4 protein induction despite mRNA induction in primary hepatocytes exposed to rifabutin as a possible explanation for its low interaction risk in vivo |c Julie Nilles, Dirk Theile, Johanna Weiss, Walter E. Haefeli, Stephanie Ruez |
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| 520 | |a Rifampicin is a strong inducer of cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp/ABCB1), leading to profound drug-drug interactions. In contrast, the chemically related rifabutin does not show such pronounced induction properties in vivo. The aim of our study was to conduct a comprehensive analysis of the different induction potentials of rifampicin and rifabutin in primary human hepatocytes and to analyze the mechanism of potential differences. Therefore, we evaluated CYP3A4/ABCB1 mRNA expression (polymerase chain reaction), CYP3A4/P-gp protein expression (immunoaffinity-liquid chromatography-mass spectrometry, IA-LC-MS/MS), CYP3A4 activity (testosterone hydroxylation), and considered intracellular drug uptake after treatment with increasing rifamycin concentrations (0.01-10 µM). Furthermore, rifamycin effects on the protein levels of CYP2C8, CYP2C9, and CYP2C19 were analyzed (IA-LC-MS/MS). Mechanistic analysis included the evaluation of possible suicide CYP3A4 inhibition (IC50 shift assay) and drug impact on translational efficiency (cell-free luminescence assays). Rifabutin accumulated 6- to 15-fold higher in hepatocytes than rifampicin, but induced CYP3A4 mRNA comparably to rifampicin (e. g. rifampicin 61-fold vs. rifabutin 44-fold, 72 h). While rifampicin for example enhanced protein (10 µM: 21-fold) and activity levels considerably (53-fold), rifabutin only slightly increased CYP3A4 protein expression (10 µM: 3.3-fold) or activity (11-fold) compared to rifampicin after 72 h. Both rifamycins similarly influenced expression of other eliminating proteins. A potential CYP3A4 suicide inhibition by a specific rifabutin metabolite or disruption of ribosome function were excluded experimentally. In conclusion, the lack of protein enhancement, could explain rifabutin's weaker induction-related drug-drug interaction risk in vivo. | ||
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| 650 | 4 | |a ATP Binding Cassette Transporter, Subfamily B, Member 1 | |
| 650 | 4 | |a Cells, Cultured | |
| 650 | 4 | |a CYP3A4 | |
| 650 | 4 | |a Cytochrome P-450 CYP3A | |
| 650 | 4 | |a Cytochrome P-450 CYP3A Inducers | |
| 650 | 4 | |a Drug Interactions | |
| 650 | 4 | |a Enzyme Induction | |
| 650 | 4 | |a Hepatocytes | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Induction | |
| 650 | 4 | |a Male | |
| 650 | 4 | |a P-gp | |
| 650 | 4 | |a Primary human hepatocyte | |
| 650 | 4 | |a Rifabutin | |
| 650 | 4 | |a Rifampicin | |
| 650 | 4 | |a Rifampin | |
| 650 | 4 | |a RNA, Messenger | |
| 650 | 4 | |a Tandem Mass Spectrometry | |
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